Methods and compositions for self-regulated release of active pharmaceutical ingredient

ABSTRACT

An abuse deterrent pharmaceutical composition including an acid soluble salt of a pharmaceutically active ingredient and a buffering ingredient; wherein the acid soluble salt of the pharmaceutically active ingredient and the buffering ingredient retard release of the pharmaceutically active ingredient when the composition is ingested in excess of an intended dosage.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/212,255, filed Aug. 31, 2015, the content of which is incorporatedherein in its entirety by reference thereto.

BACKGROUND OF THE INVENTION

The class of drugs exhibiting opium or morphine-like properties arereferred to as opioids, or opioid agonists. As agonists, certain drugsare characterized as interacting with stereo specific and saturablebinding sites in the brain and other body tissues and organs. Endogenousopioid-like peptides are present in areas of the central nervous systemthat are presumed to be related to the perception of pain; to movement,mood and behavior; and to the regulation of neuroendocrinologicalfunctions. Three classical opioid receptor types, mu (μ), delta (δ), andkappa (κ), have been studied extensively. Each of these receptors has aunique anatomical distribution in the brain, spinal cord, and theperiphery. Most of the clinically used opioids are relatively selectivefor μ receptors, reflecting their similarity to morphine. However,opioid containing drugs that are relatively selective for a particularreceptor subtype at standard therapeutic doses will often interact withmultiple receptor subtypes when given at sufficiently high doses,leading to possible changes in their pharmacological effect. This isespecially true as opioid doses are escalated to overcome tolerance.

The potential for the development of tolerance, physical and/orpsychological dependence (i.e., addiction) with repeated opioid use is acharacteristic feature of most drugs containing opioid analgesics. Thepossibility of developing addiction is one of the major concerns in theuse of opioids for the management of pain. Another major concernassociated with the use of opioids is the diversion of these drugs froma patient in legitimate pain to other individuals (non-patients) forrecreational purposes.

Drug abusers and/or addicts typically may take a solid dosage formintended for oral administration containing one or more opioidanalgesics and crush, shear, grind, chew, dissolve and/or heat, extractor otherwise tamper with or damage the dosage unit so that a significantportion or even the entire amount of the active drug becomes availablefor administration by 1) injection, 2) inhalation, and/or 3) oralconsumption in amounts exceeding the typical therapeutic dose for suchdrugs.

There are three basic patterns of behavior leading to opioid abuse. Thefirst involves individuals whose opioid drug use begins in the contextof legitimate medical treatment and who obtain their initial drugsupplies through prescriptions from appropriately licensed health careproviders. Through an insidious process these individuals may ultimatelybegin seeking prescription drug supplies far exceeding their legitimatemedical needs from multiple health care providers and/or pharmaciesand/or from illicit sources diverted from otherwise legal drugdistribution channels. The second pattern of abuse begins withexperimental or “recreational” drug users seeking a “high” with nolegitimate medical indication for drugs subject to abuse. A thirdpattern of abuse involves users who begin in one or another of thepreceding ways and ultimately switch to orally administered drugsobtained from organized and legitimate addiction treatment programs.

There are various routes of administration an abuser may commonly employto abuse an opioid containing drug formulation. The most common methodsinclude 1) parenteral (e.g. intravenous injection), 2) intranasal (e.g.,snorting), and 3) repeated oral ingestion of excessive quantities, forexample, of orally administered tablets or capsules. One mode of abuseof oral solid drugs involves the extraction of the opioid component fromthe dosage form by first mixing the dosage form with a suitable solvent(e.g., water), and then subsequently extracting the opioid componentfrom the mixture for use in a solution suitable for intravenousinjection of the opioid to achieve a “high.”

Attempts have been made to diminish the abuse potential of orallyadministered drugs. These attempts generally centered on the inclusionin the oral dosage form of an antagonist which is not orally active butwhich will substantially block the effects of the drug if one attemptsto dissolve the drug and administer it parenterally.

Despite all attempts, the misuse and abuse of pharmaceutical productscontinues to increase. Clearly there is a growing need for novel andeffective methods and compositions to deter abuse of pharmaceuticalproducts (e.g., orally administered pharmaceutical products) includingbut not limited to immediate release, sustained or extended release anddelayed release formulations for drugs subject to abuse. In particular,such methods and compositions would be useful for opioid analgesics, forpatients seeking drug therapy, which deter abuse and minimizes orreduces the potential for physical or psychological dependency.

SUMMARY OF THE INVENTION

According to some embodiments of the present invention, an abusedeterrent pharmaceutical composition includes an acid soluble salt of apharmaceutically active ingredient and a buffering ingredient. In someembodiments, the acid soluble salt of the pharmaceutically activeingredient and the buffering ingredient retard release of thepharmaceutically active ingredient when the composition is ingested inexcess of an intended dosage. In some embodiments, the acid soluble saltof the pharmaceutically active ingredient and the buffering ingredientretard release of the pharmaceutically active ingredient when three unitdoses or greater of the composition is ingested.

In some embodiments, the pharmaceutically active ingredient is a drugsusceptible to abuse. In some embodiments, the pharmaceutically activeingredient is a drug having a narrow therapeutic index. In someembodiments, the pharmaceutically active ingredient is an opioid. Insome embodiments, the acid soluble salt is a pamoate salt and/or axinafoate salt.

In some embodiments, the composition further includes an acid solubleingredient. In some embodiments, the acid soluble ingredient may includecalcium carbonate, cationic copolymer, or combinations thereof. Incertain embodiments, the acid soluble ingredient includes a cationiccopolymer based on dimethylaminoethyl methacrylate, butyl methacrylate,and methyl methacrylate. The acid soluble ingredient may be present inan amount of about 1 wt % to about 40 wt % of the pharmaceuticalcomposition.

In some embodiments, the acid soluble salt of the pharmaceuticallyactive ingredient is contained within a matrix of the acid solubleingredient.

In certain embodiments, the buffering ingredient may include calciumcarbonate, sodium bicarbonate, magnesium oxide, tribasic sodiumphosphate, or combinations thereof. The buffering ingredient may bepresent in an amount of about 45 wt % to about 95 wt %.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood by examining thefollowing figures which illustrate certain properties of the presentinvention wherein:

FIG. 1 shows the effect of calcium carbonate on pH of a dissolutionmedium over time.

FIG. 2 shows the effect of dissolution medium on the release of anactive ingredient from calcium carbonate granules.

FIG. 3 shows the release of an active ingredient from cationic copolymergranules.

FIG. 4 shows the variation of pH of a dissolution medium when multipletablets are added.

FIG. 5 shows a comparison of an in vitro active ingredient release fromsingle and multiple table administrations.

With reference to the Figures, features that are the same across theFigures are denoted with the same reference numbers.

DETAILED DESCRIPTION OF THE INVENTION

In some embodiments, formulations of the present invention are designedto block or thwart the effects caused by intentional or unintentionalover-ingestion of drug products. Under normal dosing conditions theinventive formulations may allow for the complete and/or bioequivalentoral delivery of the desired drug dose. However when excess doses areingested, either intentionally or unintentionally, the inventiveformulations may work to either slow or block the release and subsequentabsorption of the excessive doses. Thus, in the case of intentionalover-ingestion where a drug abuser would consume excess doses of anabused drug to experience a euphoric effect, the effect would besignificantly reduced for the inventive formulations compared to doseswhich freely release the excess drug of abuse. In this way, theinventive formulation may work as a deterrent from abusing the inventiveformulations for the purpose of achieving the euphoric effect. Yet thepatient who uses the invention as directed will receive the desiredtherapeutic treatment.

In general, and as described in more detail herein, pharmaceuticalformulations of the present invention may be designed with one or morecomponents to control release and/or absorption of an activepharmaceutical ingredient. In some embodiments, a pharmaceuticalformulation may be designed with a pH modifying feature and/or a pHdependent solubility feature. A pH modifying feature may impact releaseand/or absorption of an active ingredient by modifying the pH of thegastric environment based on whether the pharmaceutical composition istaken at an appropriate dosage amount or in excess. A pH modifyingfeature may be provided by inclusion of one or more buffering and/orantacid ingredients in the pharmaceutical composition. A pH dependentsolubility feature may impact release and/or absorption of an activeingredient by containing or releasing the active pharmaceuticalingredient, depending on the pH of the gastric environment. A pHdependent solubility feature may be provided by inclusion of one or moreacid soluble ingredients in the pharmaceutical composition and/or byincluding the pharmaceutically active ingredient in an acid soluble saltform.

Components

Active Pharmaceutical Ingredients

Any drug, therapeutically acceptable drug salt, drug derivative, druganalog, drug homologue, or polymorph can be used in the presentinvention. Suitable drugs for use with the present invention can befound in the Physician's Desk Reference, 59th Edition, the content ofwhich is hereby incorporated by reference. In one embodiment, the drugis an orally administered drug.

In certain embodiments, drugs susceptible to abuse are used. Drugscommonly susceptible to abuse include psychoactive drugs and analgesics,including but not limited to opioids, opiates, stimulants,tranquilizers, sedatives, anxiolytics, narcotics and drugs that cancause psychological and/or physical dependence. In one embodiment, thedrug for use in the present invention can include amphetamines,amphetamine-like compounds, benzodiazepines, and methyl phenidate orcombinations thereof. In another embodiment, the present invention caninclude any of the resolved isomers of the drugs described herein,and/or salts thereof.

A drug for use in the present invention which can be susceptible toabuse can be one or more of the following: alfentanil, amphetamines,buprenorphine, butorphanol, carfentanil, codeine, dezocine,diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate,diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol,lofentanil, meperidine, methadone, methylphenidate, morphine,nalbuphine, nalmefene, oxycodone, oxymorphone, pentazocine, pethidine,propoxyphene, remifentanil, sufentanil, tilidine, and tramodol, salts,derivatives, analogs, homologues, polymorphs thereof, and mixtures ofany of the foregoing.

In another embodiment a drug for use with the present invention whichcan be susceptible to abuse includes one or more of the following:dextromethorphan (3-Methoxy-17-methy-9a, 13a, 1 4a-morphinanhydrobromide monohydrate),N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)-ethyl]-4-methoxymethyl-4-piperidyl}propionanilide (alfentanil), 5,5-diallyl barbituric acid (allobarbital),allylprodine, alpha-prodine,8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine(alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-α-methylphenethylamine (amphetamine), 2-(α-methylphenethyl-amino)-2-phenylacetonitrile (amphetaminil), 5-ethyl-5-isopentyl barbituric acid(amobarbital), anileridine, apocodeine, 5,5-diethyl barbituric acid(barbital), benzylmorphine, bezitramide,7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepin-2(3H)-one (bromazepam),2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine(brotizolam),17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-endo-ethanomorphinan-3-ol(buprenorphine), 5-butyl-5-ethyl barbituric acid (butobarbital),butorphanol,(7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-dimethylcarbamate (camazepam), (1S,2S)-2-amino-1-phenyl-1-propanol(cathine/D-norpseudoephedrine),7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine-4 oxide(chlordiazepoxide),7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione(clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-benzodiazepin-2(3H)-one(clonazepam), clonitazene,7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylicacid (clorazepate),5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]-diazepin-2(3H)-one(clotiazepam),10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one(cloxazolam), (−)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropane carboxylate(cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine),5-(1-cyclohexenyl)-5-ethyl barbituric acid (cyclobarbital), cyclorphan,cyprenorphine,7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(delorazepam), desomorphine, dextromoramide,(+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl) propionate(dextropropoxyphene), dezocine, diampromide, diamorphone,7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam),4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine),4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol,dimephetamol [sic-Tr.Ed.], dimethyl thiambutene, dioxaphetyl butyrate,dipipanone,(6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(dronabinol), eptazocine,8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(estazolam), ethoheptazine, ethyl methyl thiambutene,ethyl-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepin-3-carboxylate](ethyl loflazepate), 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol(ethylmorphine), etonitrazene,4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol(etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine(fencamfamine), 7-[2-(α-methylphenethylamino)-ethyl] theophylline(fenethylline), 3-(α-methylphenethylamino) propionitrile (fenproporex),N-(1-phenethyl-4-piperidyl) propionanilide (fentanyl),7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(fludiazepam),5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2-(3H)-one(flunitrazepam),7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one(flurazepam),7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one(halazepam),10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one(haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone(hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone(hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan,11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepin-4,7(6H)-dione(ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone(ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate(levacetylmethadol (LAAM)), (−)-6-dimethylamino-4,4-diphenyl-3-heptanone(levomethadone), (−)-17-methyl-3-morphinanol (levorphanol), levophenacylmorphan, lofentanil,6-(2-chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2a][1,4]benzodiazepin-1(4H)-one(loprazolam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one(lorazepam),7-chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(lormetazepam),5-(4-chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol(mazindol), 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine(medazepam), N-(3-chloropropyl)-α-methylphenetylamine (mefenorex),meperidine, 2-methyl-2-propyl trimethylene dicarbamate (meprobamate),meptazinol, metazocine, methylmorphine, N,α-dimethylphenethylamine(methamphetamine), (±)-6-dimethylamino-4,4-diphenyl-3-heptanone(methadone), 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone),methyl-[2-phenyl-2-(2-piperidyl)acetate] (methyl phenidate),5-ethyl-1-methyl-5-phenyl barbituric acid (methyl phenobarbital),3,3-diethyl-5-methyl-2,4-piperidinedione (methyprylon), metopon,8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine(midazolam), 2-(benzhydrylsulfinyl) acetamide (modafinil),4,5α-epoxy-17-methyl-7-morphinene-3,6α-diol (morphine), myrophine,(±)-trans-3-(1,1-dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9(6αH)-one(nabilone), nalbuphen, nalorphine, narceine, nicomorphine,1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nimetazepam),7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (nitrazepam),7-chloro-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (nordazepam),norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone (normethadone),normorphine, norpipanone, the coagulated juice of the plants belongingto the species Papaver somniferum (opium),7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (oxazepam),(cis-trans)-10-chloro-2,3,7,1b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one(oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone(oxycodone), oxymorphone, plants and plant parts of the plants belongingto the species Papaver somniferum (including the subspecies setigerum)(Papaver somniferum), papaveretum, 2-imino-5-phenyl-4-oxazolidinone(pemoline),1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol(pentazocine), 5-ethyl-5-(1-methylbutyl) barbituric acid(pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidine-carboxylate)(pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, pholcodeine, 3-methyl-2-phenyl morpholine (phenmetrazine),5-ethyl-5-phenyl barbituric acid (phenobarbital), α,α-dimethylphenethylamine (phentermine),7-chloro-5-phenyl-1-(2-propinyl)-1H-1,4-benzodiazepin-2(3H)-one(pinazepam), α-(2-piperidyl)benzhydryl alcohol (pipradol),1′-(3-cyano-3,3-diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide(piritramide),7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one(prazepam), profadol, proheptazine, promedol, properidine, propoxyphene,N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl) propionamide,methyl-{3-[4-methoxycarbonyl-4-(N-phenylpropaneamido)piperidino]propanoate}(remifentanil), 5-sec.-butyl-5-ethyl barbituric acid (secbutabarbital),5-allyl-5-(1-methylbutyl) barbituric acid (secobarbital),N-{4-methoxymethyl-1-[2-(2-thienyl)ethyl]-4-piperidyl} propionanilide(sufentanil),7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one(temazepam),7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one(tetrazepam),ethyl-(2-dimethylamino-1-phenyl-3-cyclohexane-1-carboxylate) (tilidine(cis and trans)), tramadol,8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine(triazolam), 5-(1-methylbutyl)-5-vinyl barbituric acid (vinylbital),(1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl) phenol,(1R,2R,4S)-2-[dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol, each optionally in the form of correspondingstereoisomeric compounds as well as corresponding derivatives,especially esters or ethers, and all being physiologically compatiblecompounds, especially salts and solvates.

In some embodiments, a pharmaceutical composition includes an acidsoluble salt of an active pharmaceutical ingredient. In someembodiments, a pharmaceutical composition includes an acid soluble saltof one or more opioids such as hydrocodone, hydromorphone, morphine andoxycodone. In some embodiments, suitable acid soluble salts includeorganic acid addition salts. Suitable salts may include, but are notlimited to, pamoate, xinafoate, and combinations thereof. Acid solublesalts are understood to be soluble in acidic solutions. Acidic solutionsmay be considered those having a pH of about 1 to about 4. In someembodiments, the acid soluble salt is less soluble in slightly acidic,neutral, and/or basic solutions, i.e., those having a pH of greater thanabout 4.

In one embodiment, a pharmaceutical composition of the present inventionincludes one or more opioids such as hydrocodone, hydromorphone,morphine and oxycodone and/or salts thereof, as the therapeuticallyactive ingredient. Typically when processed into a suitable dosage form,as described in more detail below, the drug can be present in suchdosage forms in an amount normally prescribed, typically about 0.5 toabout 25 percent on a dry weight basis, based on the total weight of theformulation.

With respect to analgesics in unit dose form, such drugs may be presentin a pharmaceutically acceptable amount; standard doses of such drugsare generally known in the art and are disclosed, for example, in theUnited States Pharmacopeia and National Formulary (USP 36-NF 31).Rockville, Md.: United States Pharmacopeia Convention; 2013, which isincorporated by reference herein in its entirety. In some embodiments,such drugs may be present in an amount of about 5, 25, 50, 75, 100, 125,150, 175 or 200 mg. In some embodiments, the drug can be present in anamount from about 5 to about 500 mg or about 5 to about 200 mg. In someembodiments, a dosage form contains an appropriate amount of drug toprovide a therapeutic effect.

In some embodiments, a pharmaceutically active ingredient may include adrug having a narrow therapeutic index. Drugs having a narrowtherapeutic index may include but are not limited to aminophylline,carbamazepine, clindamycin, clonidine, digoxin, disopyramide,dyphylinne, guanthidine, isoetharine mesylate, isoproterenol,levothyroxine, lithium carbonate, metaproterenol, minoxidil,oxytriphylline, phenytoin, pasosin, primidone, procainamide, quinidinegluconate, theophylline, valproic acid, valproate sodium and warfarinsodium and the like. With respect to drugs having a narrow therapeuticdose in unit dose form, such drugs may be present in a pharmaceuticallyacceptable amount; standard doses of such drugs are generally known inthe art and are disclosed, for example, in the United StatesPharmacopeia and National Formulary (USP 36-NF 31). Rockville, Md.:United States Pharmacopeia Convention; 2013, which is incorporated byreference herein in its entirety. In some embodiments, such drugs may bepresent in an amount of about 0.025, 0.05, 0.1, 0.2, 0.3, 0.5, 1, 2,2.5, 3, 4, 5, 6, 7.5, 10, 25, 50, 75, 100, 125, 150, 175, 200, and 250mg. In some embodiments, the drug can be present in an amount of fromabout 0.01 to about 1000 mg or about 0.05 to about 500 mg. In someembodiments, a dosage form contains an appropriate amount of drug toprovide a therapeutic effect.

Component Soluble in Acidic Solutions

In some embodiments, pharmaceutical compositions of the presentinvention include one or more components which are soluble in acidicsolutions. Acidic solutions may be considered those having a pH of about1 to about 4. In some embodiments, the acid soluble component is lesssoluble in slightly acidic, neutral, and/or basic solutions, i.e., thosehaving a pH of greater than about 4.

In some embodiments, an acid soluble component is included in apharmaceutical composition in the form of particle matrix with an activepharmaceutical ingredient. The acid soluble ingredient may be includedin the pharmaceutical composition in an amount sufficient to form thismatrix. In some embodiments, the active ingredient is sequestered withinthe acid soluble component. The acid soluble component may impactrelease of the active pharmaceutical ingredient depending on the pH ofthe environment, which is raised or maintained by the buffering and/orantacid ingredient as a function of the amount of the pharmaceuticalcomposition ingested: when the pharmaceutical composition is ingested inan appropriate dosage amount, the pH buffering ingredient is not presentin an amount sufficient to alter or sufficiently raise thegastrointestinal pH, and the acid soluble component dissolves andreleases the active pharmaceutical ingredient; when the pharmaceuticalcomponent is ingested in an excess amount, the pH buffering ingredientis present in an amount sufficient to raise the gastrointestinal pH,thereby preventing the acid soluble ingredient from dissolving andreleasing the active pharmaceutical ingredient.

In some embodiments, an acid soluble component is included in thepharmaceutical composition an amount of about 1 wt % to about 50 wt %;about 1 wt % to about 48 wt %; about 1 wt % to about 46 wt %; about 1 wt% to about 44 wt %; about 1 wt % to about 42 wt %; about 1 wt % to about40 wt %; about 2 wt % to about 38 wt %; about 4 wt % to about 36 wt %;about 6 wt % to about 34 wt %; about 8 wt % to about 32 wt %; about 10wt % to about 30 wt %; about 12 wt % to about 28 wt %; about 14 wt % toabout 26 wt %; about 16 wt % to about 24 wt %; about 18 wt % to about 22wt %; about 1 wt %; about 2 wt %; about 4 wt %; about 6 wt %; about 8 wt%; about 10 wt %; about 12 wt %; about 14 wt %; about 16 wt %; about 18wt %; about 20 wt %; about 22 wt %; about 24 wt %; about 26 wt %; about28 wt %; about 30 wt %; about 32 wt %; about 34 wt %; about 36 wt %;about 38 wt %; about 40 wt %; about 42 wt %; about 44 wt %; about 46 wt%; about 48 wt %; or about 50 wt %.

Examples of suitable acid soluble components include calcium carbonate,chitosan, cationic copolymers of dimethylaminoethyl methacrylate, butylmethacrylate, and methyl methacrylate such as, for example, Eudragit® EPO, Eudragit® E100, and Eudragit® E 12.5, di and tribasic calciumphosphate, and magnesium hydroxide.

Buffering and/or Antacid Ingredients

In some embodiments, pharmaceutical compositions of the presentinvention include one or more buffering and/or antacid ingredients. Suchingredient may result in an elevation in stomach pH if thepharmaceutical composition is consumed in adequate amounts. In someembodiments, such ingredient may result in rapid and sustained elevationof stomach pH to a pH of greater than about 4 when the pharmaceuticalcomposition is consumed in adequate amounts.

In some embodiments, a buffering and/or antacid ingredient may beincluded in an amount such that stomach pH is not affected when thepharmaceutical composition is taken in appropriate therapeutic amounts,but such that stomach pH may be elevated when the pharmaceuticalcomposition is ingested in excess amounts. In some embodiments, abuffering and/or antacid ingredient is included in the pharmaceuticalcomposition in an amount of about 45 wt % to about 95 wt %; about 50 wt% to about 90 wt %; about 55 wt % to about 85 wt %; about 60 wt % toabout 80 wt %; about 65 wt % to about 75 wt %; about 45 wt %; about 50wt %; about 55 wt %; about 60 wt %; about 65 wt %; about 70 wt %; about75 wt %; about 80 wt %; about 85 wt %; about 90 wt %; or about 95 wt %.

Examples of suitable buffering and/or antacid ingredients include butare not limited to aluminum hydroxide, bismuth aluminate, bismuthcarbonate, bismuth subcarbonate, bismuth subgallate, bismuth subnitrate,calcium carbonate, calcium phosphate, dibasic calcium phosphate,dihydroxyaluminum aminoacetate, dihydroxyaluminum sodium carbonate,glycine, magnesium glycinate, magnesium hydroxide, magnesium oxide,potassium bicarbonate, sodium bicarbonate, sodium potassium tartrate,tribasic sodium phosphate and tricalcium phosphate.

In some embodiments, one ingredient may act as both an acid solubleingredient and a buffering and/or antacid ingredient. Examples of suchsuitable ingredients include calcium carbonate, di and tribasic calciumphosphate, and magnesium hydroxide.

Additional Ingredients

The present invention can also optionally include other ingredients toenhance dosage form manufacture from a pharmaceutical composition of thepresent invention and/or alter the release profile of a dosage formincluding a pharmaceutical composition of the present invention.

Some embodiments of the present invention include one or morepharmaceutically acceptable fillers/diluents. In one embodiment, AvicelPH (Microcrystalline cellulose) is a filler used in the formulation. TheAvicel PH can have an average particle size ranging from 20 to about 200μm, preferably about 100 μm. The density can range from about 1.512 toabout 1.668 g/cm³. The Avicel PH should have molecular weight of about36,000. Avicel PH effectiveness is optimal when it is present in anamount of from about 10 to 65 percent, by weight on a solid basis, ofthe formulation. Typical fillers can be present in amounts from 10 to 65percent by weight on a dry weight basis of the total composition. Otheringredients can include sugars and/or polyols. Lactose having a particlesize of about 20 to about 400 microns and a density of about 0.3 toabout 0.9 g/ml can also be included.

In some embodiments of the invention, the fillers which can be presentat about 10 to 65 percent by weight on a dry weight basis, also functionas binders in that they not only impart cohesive properties to thematerial within the formulation, but can also increase the bulk weightof a directly compressible formulation (as described below) to achievean acceptable formulation weight for direct compression. In someembodiments, additional fillers need not provide the same level ofcohesive properties as the binders selected, but can be capable ofcontributing to formulation homogeneity and resist segregation from theformulation once blended. Further, preferred fillers do not have adetrimental effect on the flowability of the composition or dissolutionprofile of the formed tablets.

In one embodiment, the present invention can include one or morepharmaceutically acceptable disintegrants. Such disintegrants are knownto a skilled artisan. In the present invention, disintegrants caninclude, but are not limited to, sodium starch glycolate (Explotab®)having a particle size of about 104 microns and a density of about 0.756g/ml, starch (e.g., Starch 21) having a particle size of about 2 toabout 32 microns and a density of about 0.462 g/ml, Crospovidone® havinga particle size of about 400 microns and a density of about 1.22 g/ml,and croscarmellose sodium (Ac-Di-Sol) having a particle size of about 37to about 73.7 microns and a density of about 0.529 g/ml. Thedisintegrant selected should contribute to the compressibility,flowability and homogeneity of the formulation. Further the disintegrantcan minimize segregation and provide an immediate release profile to theformulation. In some embodiments, the disintegrant(s) are present in anamount from about 2 to about 25 percent by weight on a solid basis ofthe directly compressible formulation. Furthermore, antacids added tothe formulations may aid in tablet disintegration when the tablet isintroduced to a low pH environment through the effervescense of theantacid ingredient, thus potentially reducing the requirement foradditional disintegrants.

In one embodiment, the present invention can include one or morepharmaceutically acceptable glidants, including but not limited tocolloidal silicon dioxide. In one embodiment, colloidal silicon dioxide(Cab-O-Sil®) having a density of about 0.029 to about 0.040 g/ml can beused to improve the flow characteristics of the formulation. Suchglidants can be provided in an amount of from about 0.1 to about 1percent by weight of the formulation on a solid basis. It will beunderstood, based on this invention, however, that while colloidalsilicon dioxide is one particular glidant, other glidants having similarproperties which are known or to be developed could be used providedthey are compatible with other excipients and the active ingredient inthe formulation and which do not significantly affect the flowability,homogeneity and compressibility of the formulation.

In one embodiment, the present invention can include one or morepharmaceutically acceptable lubricants, including but not limited tomagnesium stearate. In one embodiment, the magnesium stearate has aparticle size of about 450 to about 550 microns and a density of about1.00 to about 1.80 g/ml. In one embodiment, magnesium stearate cancontribute to reducing friction between a die wall and a pharmaceuticalcomposition of the present invention during compression and can ease theejection of the tablets, thereby facilitating processing. In someembodiments, the lubricant resists adhesion to punches and dies and/oraid in the flow of the powder in a hopper and/or into a die. In anembodiment of the present invention, magnesium stearate having aparticle size of from about 5 to about 50 microns and a density of fromabout 0.1 to about 1.1 g/ml is used in a pharmaceutical composition. Incertain embodiments, a lubricant should make up from about 0.1 to about2 percent by weight of the formulation on a solid basis. Suitablelubricants are stable and do not polymerize within the formulation oncecombined. Other lubricants known in the art or to be developed whichexhibit acceptable or comparable properties include stearic acid,hydrogenated oils, sodium stearyl fumarate, polyethylene glycols, andLubritab®.

In certain embodiments, the most important criteria for selection of theexcipients are that the excipients should achieve good contentuniformity and release the active ingredient as desired. The excipients,by having excellent binding properties, and homogeneity, as well as goodcompressibility, cohesiveness and flowability in blended form, minimizesegregation of powders in the hopper during compression.

Controlled Drug Release Dosage Forms

As described herein, pharmaceutical formulations of the presentinvention may be formulated to slow or block the release and subsequentabsorption of excessive doses of an active pharmaceutical ingredient. Insome embodiments, a pharmaceutical formulation may be designed with a pHmodifying feature and/or a pH dependent solubility feature. A pHmodifying feature may impact release and/or absorption of an activeingredient by modifying the pH of the gastric environment based onwhether the pharmaceutical composition is taken in an appropriate dosageamount or in excess. A pH modifying feature may be provided by inclusionof one or more buffering and/or antacid ingredients in thepharmaceutical composition. A pH dependent solubility feature may impactrelease and/or absorption of an active ingredient by containing orreleasing the active pharmaceutical ingredient, depending on the pH ofthe gastrointestinal environment. A pH dependent solubility feature maybe provided by inclusion of one or more pH soluble ingredients in thepharmaceutical composition. In some embodiments, the pH dependentsolubility feature may be a pharmaceutically active ingredient, forexample, in the form of an acid soluble salt.

In some embodiments, the pharmaceutical composition may be formulatedsuch that when the composition is taken in appropriate amounts, a pHmodifying feature has minimal impact (i.e., the pH of the gastricenvironment is not substantially modified or is maintained at adesirable level) and a pH dependent solubility feature has a maximalimpact (i.e., the active pharmaceutical ingredient is released), therebyallowing release and/or absorption of the active ingredient. However,when the pharmaceutical composition is ingested in excess, in someembodiments the composition is formulated such that the pH modifyingfeature has a maximal impact (i.e., the pH of the gastric environment israised) and the pH dependent solubility feature has a minimal impact(i.e., the acid solubility ingredient is not soluble and therefore doesnot dissolve), thereby thwarting release and/or absorption of the activeingredient.

In some embodiments, a pharmaceutical composition may be prepared byintimately mixing the active pharmaceutical ingredient with an acidsoluble ingredient(s) by any suitable process (i.e. dry or wetgranulation, hot melt extrusion, etc.) such that a particulate matrix isformed in a particulate form. The release of the drug from this matrixmay then be controlled by the immediate pH environment surrounding thematrix when the pharmaceutical composition is ingested. In a low pHenvironment (i.e., pH 1-4), the matrix may be likely to dissolve andrelease the drug rapidly; however, in a higher pH environment (i.e.,pH>4) the matrix is likely to be insoluble and the release of drug willbe retarded and potentially incomplete, thereby diminishing the level ofthe drug absorbed.

In some embodiments, the pharmaceutical composition may be prepared byincluding a pharmaceutically active ingredient in the form of an acidsoluble salt. The release of the active ingredient from the salt formmay then be controlled by the immediate pH environment surrounding theactive ingredient when the pharmaceutical composition is ingested. In alow pH environment (i.e., pH 1-4), the salt form may be likely torelease the drug rapidly; however, in a higher pH environment (i.e.,pH>4) the salt form is likely to be insoluble and the release of drugwill be retarded and potentially incomplete, thereby diminishing thelevel of the drug absorbed.

In some embodiments, for a single dosage unit, the required amount ofacid soluble drug matrix and/or pharmaceutically active ingredient inthe form of an acid soluble salt is further mixed with buffering and/orantacid ingredient(s) in a quantity sufficient such that when the singledose unit is ingested, the buffering and/or antacid ingredient(s) willneutralize stomach pH to a point that the stomach pH remains in a rangebetween pH 1-4. The acid soluble drug matrix/antacid/buffer blend and/orthe acid soluble pharmaceutically active salt form/antacid/buffer blendmay be formed into an oral solid dose form such as a tablet or capsulebut not limited to said dosage forms.

As a result, a pharmaceutical composition may be formulated having a pHmodifying feature and a pH dependant solubility feature such that, undernormal dosing conditions (i.e., one or two tablets), when a single doseis ingested, the buffer/antacid ingredient(s) neutralize a portion ofthe stomach acid, however the stomach acid remains in a range between pH1-4. Under these conditions, the acid soluble drug matrix and/or theacid soluble pharmaceutically active salt form is soluble in the acidicstomach environment and the drug may be rapidly released in the stomachand absorbed into the bloodstream.

Under conditions where excess doses are ingested, intentionally orunintentionally, (i.e., three tablets or greater), the quantity ofbuffers and/or antacid ingredient(s) from over-ingestion may now besufficient to cause a rapid and sustainable increase in stomach pH (>pH4). Thus the acid soluble drug matrix and/or the acid solublepharmaceutically active salt form may be less soluble in the higher pHstomach environment and the release of drug from the matrix may besuppressed. In some embodiments, the suppression of drug from the acidsoluble matrix and/or the acid soluble pharmaceutically active salt formis further aided by gastro-intestinal transit, which may transfer theacid soluble matrix particle and/or the acid soluble pharmaceuticallyactive salt form into the intestine and lower gastro-intestinal tractwhich have biologically controlled high pH environments (i.e., pH5.5-8). The overall suppression of drug release from over ingestionresults in a pharmacokinetic profile with an increase in Tmax and adecrease in Cmax when compared to an equal oral dose which releases drugin normal stomach pH (i.e., pH 1-4).

Suitable formulations and dosage forms of the present invention includebut are not limited to powders, caplets, pills, suppositories, gels,soft gelatin capsules, capsules and compressed tablets manufactured froma pharmaceutical composition of the present invention. The dosage formscan be any shape, including regular or irregular shape depending uponthe needs of the artisan.

Compressed tablets including the pharmaceutical compositions of thepresent invention can be direct compression tablets or non-directcompression tablets. In one embodiment, a dosage form of the presentinvention can be made by wet granulation, and/or dry granulation (e.g.,slugging or roller compaction). The method of preparation and type ofexcipients are selected to give the tablet formulation desired physicalcharacteristics that allow for the rapid compression of the tablets.After compression, the tablets must have a number of additionalattributes such as appearance, hardness, disintegrating ability, and anacceptable dissolution profile.

Choice of fillers and other excipients typically depend on the chemicaland physical properties of the drug, behavior of the mixture duringprocessing, and the properties of the final tablets. Adjustment of suchparameters is understood to be within the general understanding of oneskilled in the relevant art. Suitable fillers and excipients aredescribed in more detail above.

The manufacture of a dosage form of the present invention can involvedirect compression and wet and dry granulation methods, includingslugging and roller compaction.

In some embodiments, one or more components may be sequestered, asdescribed in U.S. Patent Application Publication No. 2012/0202839 whichis incorporated by reference herein in its entirety.

The present invention can be used to manufacture immediate release, andcontrolled drug release formulations. Controlled release formulationscan include delayed release, bi-modal and tri-modal release, extendedand sustained release oral solid dosage preparations.

As used herein, the term “about” is understood to mean ±10% of the valuereferenced. For example, “about 45%” is understood to literally mean40.5% to 49.5%.

As used herein, the term “bioequivalence” is understood to mean one ormore of C_(max), T_(max), or area under the concentration curve “AUC” ofa drug is within 75% to 120% of the same marker for a referenced drug.

Certain aspects of the present invention may be better understood asillustrated by the following examples, which are meant by way ofillustration and not limitation.

Example 1

Two dissolution vessels were prepared: one vessel contained 25 mEq ofHCl and a single commercially available calcium carbonate antacid tablet(Tums®), and the other vessel contained 25 mEq of HCl and five calciumcarbonate antacid tablets. The pH in each vessel was monitored and theresults are shown in FIG. 1. For the single tablet, the tablet iscompletely reacted in about 30 minutes and the dissolution of the singletablet showed no change in pH. However, the introduction of five tabletsresults in a relatively rapid rise in 10 minutes to a pH greater than4.5 and after 90 minutes, a considerable amount of non-dissolved solidwas observed in the vessel. Therefore, it has been shown that calciumcarbonate at a low level (500 mg) could completely dissolve with littleeffect on pH but with excess amounts of calcium carbonate a rapid pHincrease occurs creating a high pH environment, in which calciumcarbonate exhibits low solubility. Calcium carbonate has shown acapability as a pH modifier and pH dependent solubility.

Example 2

A challenge faced in designing a self-regulating dosage form is toinstitute regulation (i.e., slower or incomplete release) at elevated pHwithout compromising the desired rapid release rate associated withimmediate release tablets when a single dose is taken. Calcium carbonatewas evaluated both in direct blend matrix tablets and dry granulationtablets containing alprazolam, where the granule contained calciumcarbonate to control drug release and calcium carbonate outside thegranule to effect pH change. Both approaches resulted in sloweralprazolam release in single tablets at higher pH (approx. pH 6)compared to low pH (pH 1), however, in this case the release separationwas not as high as desired (FIG. 2). However, the results demonstratethat a granule may be used to control drug release depending on pHenvironment. The granules may consist of the drug along with afunctional component that inhibits erosion or disintintegration atelevated pH such that slower and/or incomplete release of the drug isobserved. The extragranular portion of the tablet may primarily containthe pH controlling agents, which need to be released and react quickly.

Example 3

Eudragit® E PO (EPO) is a cationic copolymer based on dimethylaminoethylmethacrylate, butyl methacrylate, and methyl methacrylate. Technicalliterature indicates that this polymer is soluble in acid, up to pH 5;above pH 5 it swells rather than dissolves. Dry granulations containing5% alprazolam in EPO polymer were prepared and size fractions collectedat −16 mesh and +20 mesh (16/20) and at −20 mesh and +30 mesh (20/30).Dissolution on the granulation size fractions were performed at both lowpH (pH 1.5) where EPO is soluble and at high pH (pH 6) were EPO is lesssoluble. The results are shown in FIG. 3. At low pH, irrespective of theparticle size, a rapid and complete release of alprazolam occurs within15 minutes. However at high pH, the release of alprazolam issignificantly slower and incomplete for both size fractions but slightlyelevated for the smaller fraction. It must be noted that thisdissolution simulation represents a static pH condition at the potentialpH extremes if the tablet is taken as directed (pH 1) and in excess (pH6). The next example examines a pH modifying system which doesn't affectpH when taken as directed but will rapidly increase pH whenover-ingested.

Example 4

Subsequent trials to use calcium carbonate as the primary pH modifyingagent resulted in a relatively rapid release of alprazolam in 15 minutesfrom 5% alprazolam/EPO granules (60%). Although the pH change to pH 5previously seen for calcium carbonate in 10 minutes (FIG. 1) may havebeen perceived fast, given that release of alprazolam is also rapid andcompleted in 15 minutes, calcium carbonate may not affect a pH changerapidly enough for the alprazolam/EPO granules. In earlierexperimentation, sodium bicarbonate had been shown to have a more rapidpH effect, raising acid media from a pH 1 to a pH 6 in less than 2minutes. Thus, sodium bicarbonate was added to a prototype formulationprimarily to control rapid pH elevation and calcium carbonate for a moresustained control of elevated pH. A representative formulation for theinvention is shown in the table below:

Component Wt % Wt (mg) Alprazolam (5%) in 3.195 20.00 Eudragit E PO(20/30) Sodium bicarbonate 79.87 500.0 Calcium carbonate DC 15.97 100.0Magnesium stearate 0.958 6.0 Total 100 626.0

The prototype formulation was tableted and a dynamic test was performedwhere the pH modifying agents were contained in the tablets anddynamically reacted in 0.55 N HCl media (about pH 1.6). Multiple tabletdoses both with and without self-regulation as well as a single dosewith self-regulation were tested and compared. Dissolution media pH anddrug release were monitored. As shown in FIG. 4, a rapid rise in pH inthe prototype multiple tablets was observed with a rise to pH 6occurring in less than two minutes. Thus, a rapid rise in pH can beaffected by the pH modifying agents contained in the tablet.

Furthermore, as shown in FIG. 5, a single tablet releases alprazolam in15 minutes showing that the immediate release characteristic of a singletablet is unaffected by the on-board, self-regulating system. However,multiple tablets with self-regulating show approximately a single dosereleased in 15 minute with a delayed release of the excess alprazolamover approximately 2 hours. By comparison, multiple tablets withoutself-regulating show that the entire alprazolam dose (approximately 9mg) is released in approximately 15 minutes, whereas only 20% alprazolamis released in multiple tablets with self-regulating at the same timepoint. Clearly, prototype self-regulating alprazolam tablets have beenshown to release a single dose of alprazolam as intended but multipletablets show a retardation of the release of excess doses compared toexcess doses without self-regulating.

It will be appreciated by persons skilled in the art that numerousvariations and/or modifications may be made to the invention shown inthe specific embodiments without departing from the spirit and scope ofthe invention as broadly described. Further, each and every referencecited above is hereby incorporated by reference as if fully set forthherein.

What is claimed is:
 1. An abuse deterrent pharmaceutical compositioncomprising: a. an acid soluble salt of a pharmaceutically activeingredient; and b. a buffering ingredient; wherein the acid soluble saltof the pharmaceutically active ingredient and the buffering ingredientretard release of the pharmaceutically active ingredient when thecomposition is ingested in excess of an intended dosage.
 2. Thecomposition of claim 1, wherein the pharmaceutically active ingredientcomprises a drug susceptible to abuse.
 3. The composition of claim 1,wherein the pharmaceutically active ingredient comprises a drug withnarrow therapeutic index.
 4. The composition of claim 1, wherein theacid soluble salt comprises a pamoate salt and/or a xinafoate salt. 5.The composition of claim 1, wherein the pharmaceutically activeingredient is an opioid.
 6. The composition of claim 1, furthercomprising an acid soluble ingredient.
 7. The composition of claim 1,wherein the acid soluble ingredient comprises calcium carbonate,cationic copolymer, or combinations thereof.
 8. The composition of claim1, wherein the acid soluble ingredient comprises a cationic copolymerbased on dimethylaminoethyl methacrylate, butyl methacrylate, and methylmethacrylate.
 9. The composition of claim 1, wherein the acid solublesalt of the pharmaceutically active ingredient is contained within amatrix of the acid soluble ingredient.
 10. The composition of claim 1,wherein the acid soluble ingredient is present in an amount of about 1wt % to about 40 wt % of the pharmaceutical composition.
 11. Thecomposition of claim 1, wherein the buffering ingredient comprisescalcium carbonate, sodium bicarbonate, magnesium oxide, tribasic sodiumphosphate, or combinations thereof.
 12. The composition of claim 1,wherein the buffering ingredient is present in an amount of about 45 wt% to about 95 wt %.
 13. The composition of claim 1, wherein the acidsoluble salt of the pharmaceutically active ingredient and the bufferingingredient retard release of the pharmaceutically active ingredient whenthree unit doses or greater of the composition is ingested.